The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

Yari Carlomagno, Sireesha Manne, Michael Deture, Mercedes Prudencio, Yongjie Zhang, Rana Hanna Al-Shaikh, Judith A. Dunmore, Lillian M. Daughrity, Yuping Song, Monica Castanedes-Casey, Laura J. Lewis-Tuffin, Katharine A. Nicholson, Zbigniew K. Wszolek, Dennis W. Dickson, Anthony W.P. Fitzpatrick, Leonard Petrucelli, Casey N. Cook

Research output: Contribution to journalArticlepeer-review

Abstract

Tau accumulation is a major pathological hallmark of Alzheimer's disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, we demonstrate that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology. The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay. Finally, we show that the filament cores in corticobasal degeneration (CBD) and Pick's disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.

Original languageEnglish (US)
Article number108843
JournalCell reports
Volume34
Issue number11
DOIs
StatePublished - Mar 16 2021

Keywords

  • aggregation
  • Alzheimer's disease
  • biomarker
  • corticobasal degeneration
  • filament core
  • neurofibrillary tangles
  • Pick's disease
  • real-time quaking-induced conversion
  • tau
  • tauopathy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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